Abstract Tumor-associated macrophages are key effector immune cells that promote prostate cancer progression. Studies in other cancers show that macrophage secrete cytokines, angiogenic mediators and/or metabolites to drive resistance to various therapeutics. Here we sought to determine the role of macrophage altered metabolism in driving resistance to androgen receptor (AR) targeted therapy. Unbiased transcriptomic analysis of prostate tumors following macrophage depletion revealed that macrophage infiltration was associated with molecular signatures of AR activation and cholesterol transport. These findings were recapitulated in vitro, with the co- culture of macrophages and prostate cancer cells enhancing AR nuclear localization, increasing cancer cell proliferation in androgen-deprived conditions, and reducing sensitivity to the AR antagonist, enzalutamide. We then characterized role of cholesterol in macrophage tumor cell lipid interaction and AR activation and identified the transcriptional regulator of cholesterol metabolism LXR as a novel mediator of macrophage-induced AR activation. Accordingly, we hypothesize that altered macrophage metabolism in prostate cancer drives resistance to AR-targeted therapy via LXR dependent perturbation of cholesterol transport and biosynthesis. The cholesterol exchange may be further propelled by metal ion availability in tumor microenvironment as our new findings suggested. To address this, we propose to 1) Determine the mechanisms by which macrophages drive resistance to androgen receptor targeted therapy. 2) To evaluate the therapeutic potential of targeting macrophage-tumor cell lipid interactions to overcome resistance to AR inhibitors. The goal of this project is to identify metabolic liabilities in tumor microenvironment that can be targeted to achieve cure in prostate cancer patients.

PROJECT NARRATIVE. Macrophages represent the dominant population of immune cells within prostate tumors. Here we will determine how exchange of cholesterol and metal ions drive resistance to androgen receptor targeted therapy.